Although HIV-infected long-term nonprogressors (LTNP) and those on highly active antiretroviral therapy (HAART) have undetectable virus in blood; it is known that virus persists in yet unknown tissue reservoir(s) in essentially all HIV-infected patients throughout the course of infection. A number of tissue reservoirs have been proposed to harbor HIV-1. However, emerging evidence indicates gut-associated lymphoid tissue (GALT) is the major site of viral persistence and reservoir. However, technical challenges and risks limit progress in adequately defining tissue reservoirs in HIV-infected patients. These reasons mandate an assessment of tissue reservoirs using an animal model. Previously, we established a nonhuman primate model using SIV- infected rhesus macaques of Chinese origin (Ch Rh). We found that SIVmac239 infection in Ch Rh more closely mimics HIV-1 infection than other nonhuman primate models. Further, approximately 1/3 of Ch Rh spontaneously control SIV infection despite residual virus in tissues. Recently, we have discovered that the Ch Rh is the premier animal model for studying reservoirs under HAART. The recent addition of integrase inhibitors to the HIV therapeutic arsenal has demonstrated remarkable suppression when combined with standard HAART. Furthermore, we have found that Ch Rh, when treated with anti-SIV regimens that include integrase inhibitors have maximal suppression (< 30 copies/ml) virus in plasma, a feat that had yet to be achieved in a nonhuman primate model. We now have a unique model that can be utilized to test our hypothesis that the intestinal tract is the greatest reservoir for SIV in spontaneous viral controllers or on HAART, and determine whether novel strategies of treatment lead to eventually eradicate virus from these reservoirs. Here we propose: Aim 1. Identify the cellular and tissue reservoirs in SIV-infected macaques on HAART and those that become elite controllers. Using a novel combination of RT inhibitors and integrase inhibitors we will reduce viremia to <10 RNA copies/ml in plasma of treated NP. We will quantify and compare cellular and tissue reservoirs in the intestinal tract, bone marrow, spleen, and other tissues to determine the major reservoirs, we will also analyze viral mutations and evolution among NP on HAART, without HAART and LTNP to examine their association with viral reservoir and combination antiretroviral therapy. Aim 2. Assess the potential for eradication of virus from infected hosts by combining HAART with supplemental regimens or tissue-targeted strategies in early SIV infection. Novel antiviral strategies continue to emerge for HIV infection, and we will incorporate some of the latest antiviral regimens in the SIV-macaque model. For example, we are currently testing fusion inhibitors in macaques, and these may be combined with the above therapy in an attempt to quantify the decay of cell and tissue reservoirs in macaques on multiple drug combinations. Further, we may design specific strategies to target specific sites using the knowledge gained in Aim1 to successful viral eradication. The proposed research will provide new insights into the mechanisms of HIV persistence and latency, and assess whether eradication may be a feasible goal. Finally, these data may identify useful targets for novel therapeutic or vaccine approaches. )